title: Nitric oxide-mediated intracellular growth restriction of pathogenic Rhodococcus equi can be prevented by iron.
abstract: Rhodococcus equi is an intracellular pathogen which causes pneumonia in young horses and in immunocompromised humans. R. equi arrests phagosome maturation in macrophages at a prephagolysosome stage and grows inside a privileged compartment. Here, we show that, in murine macrophages activated with gamma interferon and lipopolysaccharide, R. equi does not multiply but stays viable for at least 24 h. Whereas infection control of other intracellular pathogens by activated macrophages is executed by enhanced phagosome acidification or phagolysosome formation, by autophagy or by the interferon-inducible GTPase Irgm1, none of these mechanisms seems to control R. equi infection. Growth control by macrophage activation is fully mimicked by treatment of resting macrophages with nitric oxide donors, and inhibition of bacterial multiplication by either activation or nitric oxide donors is annihilated by cotreatment of infected macrophages with ferrous sulfate. Transcriptional analysis of the R. equi iron-regulated gene iupT demonstrates that intracellular R. equi encounters iron stress in activated, but not in resting, macrophages and that this stress is relieved by extracellular addition of ferrous sulfate. Our results suggest that nitric oxide is central to the restriction of bacterial access to iron in activated macrophages.
authors.affiliation: Cell Biology Institute, University of Bonn, Ulrich-Haberland-Str. 61 A, 53121 Bonn, Germany.
authors.forename: Kristine
authors.initials: K
authors.lastname: von Bargen
authors.forename: Jens
authors.initials: J
authors.lastname: Wohlmann
authors.forename: Gregory Alan
authors.initials: GA
authors.lastname: Taylor
authors.forename: Olaf
authors.initials: O
authors.lastname: Utermöhlen
authors.forename: Albert
authors.initials: A
authors.lastname: Haas
mesh_terms: D000193:Actinomycetales Infections / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D007501:Iron / Q000276:immunology* / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D009569:Nitric Oxide / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016929:Rhodococcus equi / Q000254:growth & development / Q000276:immunology / Q000378:metabolism
chemical_list: D009569:Nitric Oxide; D007501:Iron